Generation and Characterization of the First Murine Model of Alzheimer's Disease with Mutated AβPP Inserted in a BALB/c Background (C.B6/J-APPswe).

Background: Numerous mouse models of Alzheimer's disease (AD) are available, but all suffer from certain limitations, thus prompting further attempts. To date, no one model exists with amyloidopathy in a BALB/c strain.

Objective: To generate and characterize the C.

The effect of astaxanthin on the aging rat brain: gender-related differences in modulating inflammation.

Background: Astaxanthin (Ax) is a ketocarotenoid of the xanthophyll family with activities such as antioxidation, preservation of the integrity of cell membranes and protection of the redox state and functional integrity of mitochondria. The aim of this study was to investigate potential gender-related differences in the effect of Ax on the aging rat brain.

Results: In females, interleukin 1 beta (IL1β) was significantly lower in treated rats in both cerebral areas, and in the cerebellum, treated animals also had significantly higher IL10.

Effect of cognitive training on the expression of brain-derived neurotrophic factor in lymphocytes of mild cognitive impairment patients.

To identify biomarkers associated with cognitive stimulation of mild cognitive impairment (MCI) patients, we performed quantitative real-time reverse transcriptase polymerase chain reaction for brain-derived neurotrophic factor (BDNF) mRNA in peripheral lymphocytes of MCI and healthy subjects undergoing a multi-component cognitive training (CT) program. CT determined a significant decrease of BDNF mRNA levels in MCI (fold change=0.31) as compared to healthy subjects (fold change=0.

Early selective vulnerability of synapses and synaptic mitochondria in the hippocampal CA1 region of the Tg2576 mouse model of Alzheimer's disease.

Increasing experimental evidence indicates that synaptic alterations play a key role in cognitive decline in Alzheimer's disease (AD). Functional and structural synaptic changes progressively take place, beginning in the early phase of AD, mainly triggered by intracellular accumulation of soluble amyloid-β (Aβ) oligomers. These peptides also accumulate within mitochondria, heavily affecting their function and morphology, particularly in synaptic compartments.

Platelets in Alzheimer's disease-associated cellular senescence and inflammation.

Alzheimer's disease (AD) is a complex degenerative disorder of the brain, associated with a progressive cognitive decline. Age is the main risk factor with almost half of the population above 90 years affected by this pathology. AD and brain aging share common molecular changes, so it has been hypothesized that AD could be a form of accelerated brain aging.

Peripheral inflammatory biomarkers of Alzheimer's disease: the role of platelets.

Alzheimer's disease is an age-dependent neurodegenerative disorder characterized by loss of neurons, synaptic degeneration, senile plaques and neurofibrillary tangles. Besides these hallmarks, increased accumulation of activated microglia, astrocytes and leukocytes adhering to postcapillary venules are observed in the affected brain areas, suggesting the presence of an ongoing inflammatory process. As neuroinflammation triggers the activation of peripheral immune system, many studies have analyzed circulating inflammatory biomarkers, including basal or stimulated levels of cytokines and related molecules in blood of Alzheimer's patients, but with conflicting results.

A ketogenic diet increases succinic dehydrogenase (SDH) activity and recovers age-related decrease in numeric density of SDH-positive mitochondria in cerebellar Purkinje cells of late-adult rats.

Ketogenic diets (KDs) have been applied in the therapy of paediatric epilepsy for nearly a century. Recently, beneficial results have also been reported on metabolic disorders and neurodegeneration, designating aged individuals as possible recipients. However, KDs efficacy decrease after the suckling period, and very little is known about their impact on the aging brain.

A ketogenic diet increases succinic dehydrogenase activity in aging cardiomyocytes.

Impairment of energy metabolism and an increase of reactive oxygen species (ROS) production seem to play a major role in age-related apoptotic loss of cardiomyocytes. Succinic dehydrogenase (SDH) is an important marker of the mitochondrial capability to provide an adequate amount of ATP. Moreover, because of its unique redox properties, SDH activity contributes to maintain the reduced state of the ubiquinone pool.

Ketogenic diets cause opposing changes in synaptic morphology in CA1 hippocampus and dentate gyrus of late-adult rats.

Ketogenic diets (KDs) have beneficial effects on several diseases, such as epilepsy, mitochondriopathies, cancer, and neurodegeneration. However, little is known about their effects on aging individuals. In the present study, late-adult (19-month-old) rats were fed for 8 weeks with two medium chain triglycerides (MCT)-KDs, and the following morphologic parameters reflecting synaptic plasticity were evaluated in stratum moleculare of hippocampal CA1 region (SM CA1) and outer molecular layer of hippocampal dentate gyrus (OML DG): average area (S), numeric density (Nv(s)), and surface density (Sv) of synapses, and average volume (V), numeric density (Nv(m)), and volume density (Vv) of synaptic mitochondria.

Experimental apoptosis provides clues about the role of mitochondrial changes in neuronal death.

A quantitative morphometric study has been carried out in human neuroblastoma SK-N-BE cells to evaluate the ultrastructural features and the metabolic efficiency of mitochondria involved in the early steps of apoptosis. In mitochondria from control and apoptotic cells cytochrome oxidase (COX) activity was estimated by preferential cytochemistry. Number of mitochondria (numeric density: Nv), volume fraction occupied by mitochondria/microm3 of cytoplasm (volume density: Vv), and average mitochondrial volume (V) were calculated for both COX-positive and -negative organelles.

Reactive structural dynamics of synaptic mitochondria in ischemic delayed neuronal death.

The effect of transient global ischemia on the ultrastructural features of synaptic mitochondria at the distal dendrites of CA1 hippocampal neurons was investigated in 3-month-old rats. Sham surgery was performed on age-matched controls. The number of mitochondria/microm3 of neurophils (Nv: numeric density), the mitochondrial average size (average volume: V), and longer diameter (Fmax) as well as the overall fraction of neurophils occupied by mitochondria (volume density: Vv) were measured by computer-assisted morphometry.

Age-related decline in metabolic competence of small and medium-sized synaptic mitochondria.

A computer-assisted morphometric investigation of cytochrome oxidase (COX) activity, selectively evidenced by preferential diaminobenzidine cytochemistry, has been carried out on synaptic mitochondria in the cerebellar cortex of adult and old rats. The ratio (R) of the area of the cytochemical precipitate (CPA) to the overall area of each mitochondrion (MA) was calculated. R refers to the fraction of the inner mitochondrial membrane actively involved in cellular respiration, thus its quantitative estimation constitutes a reliable index of the mitochondrial metabolic competence (MMC).

Chronic aluminum administration to old rats results in increased levels of brain metal ions and enlarged hippocampal mossy fibers.

The effect of chronic aluminium administration (2 g/L/6 months) was investigated in the central nervous system (CNS) of old rats. The content of Al(3+), Cu(2+), Zn(2+), and Mn(2+) was measured in prosencephalon + mesencephalon, pons-medulla, and cerebellum. The area occupied by the mossy fibers in the hippocampal CA3 zone was also measured.

Cytochrome oxidase activity in hippocampal synaptic mitochondria during aging: a quantitative cytochemical investigation.

Synaptic mitochondria, cytochemically positive to cytochrome oxidase (COX) activity, were investigated by morphometric methods in the hippocampal dentate gyrus of adult and old rats. The number of mitochondria/microm(3) of tissue (Nv), the volume fraction occupied by mitochondria/microm(3) of tissue (Vv), the average mitochondrial volume (V), the longer mitochondrial diameter (F(max)), and the ratio R:mitochondrial area/overall area of the cytochemical precipitate due to COX activity were measured on COX-positive organelles. In old animals, Nv, Vv, V, and F(max) increased at a not significant extent; R was not significantly decreased.

Decay of mitochondrial metabolic competence in the aging cerebellum.

Cytochemically evidenced cytochrome oxidase activity was morphometrically measured in the cerebellar cortex of adult and old rats. The ratio (R) between the area of the precipitate due to the cytochemical reaction and the overall area of each mitochondrion was calculated. While in adult rats an inverse correlation between mitochondrial size and R values (r = -.

Role of mitochondrial deterioration in physiological and pathological brain aging.

Background: Mitochondria are widely reported to occupy a unique role in modulating cell viability, senescence and death. This is consistently supported by the multiple functions of these organelles. In addition to providing the energy for the myriad of cellular performances, mitochondria are involved in regulating thermogenesis, calcium buffering, integration of pro- and anti-apoptotic signals.

Neuronal death versus synaptic pathology in Alzheimer's disease.

Neuron and synapse numeric densities as well as the average size and surface density of the synaptic junctional areas were measured in the hippocampus and cerebellum of adult, old, and demented (Alzheimer's disease) patients. Our findings support the notion that synaptic loss represents per se a prominent and early damage affecting zones of the central nervous system reported to show a different vulnerability to age- and pathology-related changes.

Morphometric investigations of the mitochondrial damage in ceroid lipopigment accumulation due to vitamin E deficiency.

Numeric (Nv) and volume (Vv) densities, as well as the average size (skeleton: Sk) of synaptic mitochondria from adult, normally fed and adult, vitamin E deficient animals (11 months of age) were semiautomatically measured by computer-assisted morphometry in the cerebellar granular layer. Nv, Vv and the average mitochondrial volume (V) were measured on perikaryal Purkinje cell organelles preferentially stained for succinic dehydrogenase (SDH) activity. Adult vitamin E deficient animals showed a significant decrease of Nv, a significant increase of Sk and an unchanged value of Vv.

Morphometry of age pigment (lipofuscin) and of ceroid pigment deposits associated with vitamin E deficiency.

Consistent amounts of lipofuscin and of ceroid pigment associated with vitamin E deficiency are reported to represent morphological correlates of aging and increased oxidative stress. A reliable quantification of these yellow autofluorescent deposits is of critical biological significance, thus we carried out a computer-assisted morphometric study on the accumulation of lipofuscin in physiological aging and of ceroid pigment in vitamin E deficiency, respectively. The total area and the size distribution of lipofuscin or ceroid pigment deposits were measured in CA3 hippocampal pyramidal neurons of 6-, 12-, 18- and 25-month-old rats, as well as in vitamin E deficient animals of 18 months of age.

GAP-43 mRNA detection by in situ hybridization, direct and indirect in situ RT-PCR in hippocampal and cerebellar tissue sections of adult rat brain.

The growth-associated protein GAP-43 is a presynaptic membrane phosphoprotein that is expressed at high levels during development and axonal growth. To evaluate the cellular distribution of GAP-43 mRNA in the hippocampus and cerebellum of adult rats we applied in situ hybridization (ISH) as well as direct and indirect in situ RT-PCR using biotin as a reporter molecule. ISH resulted in a positive signal in most cerebellar granular cells and in 30% of hippocampal CA3 neurons.

Inverse correlation between mitochondrial size and metabolic competence: a quantitative cytochemical study of cytochrome oxidase activity.

Mitochondria are topologically closed bilayered systems where the synthesis of adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and inorganic phosphate occurs via oxidative phosphorylation. The ordered architecture (and its extension) of the mitochondria (i.e.

Beta-amyloid fragment 25-35 selectively damages platelets from patients with Alzheimer's disease.

In order to analyze the metabolic response of AD patient platelets to beta-amyloid, we have carried out fluorimetric measurements of intracellular calcium and an ultrastructural survey of platelets exposed to the beta-amyloid active fragment 25-35 (betaA(25-35)). Since it is not possible to analyze directly the damaged neurons in AD, the study of peripheral blood cells, especially platelets, may be of great value for the investigation of the toxic effects of beta-amyloid on AD neuronal cells.